Disodium 3-amino-1-hydroxypropane-1,1-diphosphonate or xe2x80x9cdisodium pamidronatexe2x80x9d has the formula: 
It is commercially available as the lyophilized pentahydrate, under the name AREDIA(copyright) from Novartis Pharmaceuticals Corp., and is used to inhibit bone resorption, i.e., to treat moderate or severe hypercalcemia associated with malignancy, with or without bone metastases. The preparation of the crystalline pentahydrate from pamidronic acid is disclosed by Stahl et al. in U.S. Pat. Nos. 4,711,880 and 4,639,338. This material is prepared by partially neutralizing a heated slurry of pamidronic acid with aqueous sodium hydroxide (NaOH) to pH 7-7.5 and then initiating crystallization at xe2x89xa750xc2x0 C. The mixture is slowly cooled to 0-5xc2x0 C. and the disodium pamidronate is collected by filtration. This product is described as having xe2x80x9cexcellent crystallinityxe2x80x9d and as being xe2x80x9ccompletely stable to storage under approximately normal ambient conditions.xe2x80x9d It comprises about 24.1-25% water.
The crystalline product (xe2x80x9cModification Exe2x80x9d) is contrasted with an amorphous product disclosed to be prepared by the general process of Jary et al. (U.S. Pat. No. 4,304,734). In Comparison Example 1 of the ""338 patent, pamidronic acid is neutralized to pH 7.4 with aqueous NaOH and the reaction mixture is concentrated to dryness under reduced pressure at 60-70xc2x0 C. and then dried at 20 mbar to constant weight. However, the amorphous product that is obtained is described as deliquescent in air, contains 12.9% of retained water and, as taught in the ""338 patent, will convert to the pentahydrate. Stahl et al. also teach the interconversion of other crystalline forms of disodium pamidronate depending upon humidity and amount of water present, which demonstrates the difficulty in utilizing preformed disodium salts of pamidronic acid for further processing into sterile pharmaceutical dosage forms.
Thus, a need exists for a simple method to prepare disodium pamidronate and dosage forms thereof that are stable to storage and suitable for reconstitution and/or intravenous infusion/injection.
The present invention provides a pharmaceutical unit dosage form comprising an aqueous solution of disodium pamidronate enclosed in a suitable container, such as an ampule or vial, under an inert atmosphere. Preferably the container is designed for xe2x80x9csingle usexe2x80x9d. Preferably, the container is formed of a material that does not contain calcium in a form that can be sequestered by the dissolved disodium pamidronate.
The present invention also provides a method for the preparation of amorphous, essentially anhydrous (xe2x89xa61-2 wt-% water) disodium pamidronate (the xe2x80x9cproductxe2x80x9d). This solid product can be stored under nitrogen at otherwise ambient conditions, and readily reconstituted with sterile water or physiological salt solutions for injection or infusion into a patient in need of treatment therewith.
The present method also comprises a method to make an aqueous solution of disodium pamidronate by addition of aqueous sodium hydroxide to a stirred slurry of pamidronic acid in an about 2:1 molar ratio of NaOH to acid, optionally comprising excess mannitol, to yield a clear solution of pH 6.5xc2x10.1. Aqueous phosphoric acid is added as needed if the pH following NaOH addition is too high. A small amount of aqueous NaOH can be added if the pH is too low. Preferably, 1 N aqueous NaOH is used.
The solution is frozen and lyophilized under reduced pressure to yield amorphous, essentially anhydrous disodium pamidronate. The product is stable when stored under dry nitrogen at otherwise ambient conditions. Preferably, the about pH 6.5 solution is filtered and aliquots are introduced into suitable container(s), then frozen (xe2x88x9225 to xe2x88x9240xc2x0 C.), lyophilized (10-25 mbar, 20-40xc2x0 C.) in situ, and the containers sealed under positive nitrogen pressure to yield a plurality of unit dosage forms of solid disodium pamidronate, optionally in admixture with mannitol.
For example, vials containing 30 mg, 60 mg and 90 mg of sterile lyophilized disodium pamidronate, each optionally containing 470 mg, 400 mg, and 375 mg of mannitol can readily be prepared and utilized as disclosed in Physician""s Desk Reference (52d ed., 1988) at pages 1824-1828.
The present invention further provides an improved method for the preparation of aqueous solutions and dosage forms of disodium pamidronate of defined composition, using pamidronic acid as a starting compound and titrating an aqueous pamidronic acid slurry having a concentration of about 0.1 to 0.5 M, preferably about 0.130 to about 0.135 M, to visual clarity at a pH of approximately 6.5 using aqueous sodium hydroxide (NaOH) or other suitable base to yield an aqueous solution of disodium pamidronate. Preferably, an about 2:1 molar ratio of NaOH or other metal hydroxide to pamidronic acid is used. Mannitol is an optional component of the slurry, preferably present in a molar excess to pamidronate as in the solutions described above, prior to lyophilization. Alternately, the solution is titrated to clarity using aqueous sodium hydroxide and the final pH adjusted to approximately 6.5xc2x10.1 using phosphoric acid as needed. The clear aqueous solution of disodium pamidronate is then filtered and packaged as unit dosage forms comprising aliquots of the filtered solution.
This aspect of the present invention entirely eliminates the generation and isolation of various metastable, hydrated, crystalline and/or amorphous physical forms of disodium pamidronate (each of which can interchange with the other, depending upon the circumstance of available moisture or temperature in the substance environment). The present invention affords stable pamidronate compositions which can be stored at temperatures of, for example, 0xc2x0 C. or less (frozen), about 2 to about 8xc2x0 C. (refrigerated), or about 20 to about 30xc2x0 C. (room temperature). The compositions can be used to prepare dosage forms suitable for therapeutic oral, rectal, transdermal, intranasal, or intravenous administration.
As used herein, the term xe2x80x9caboutxe2x80x9d incorporates inherent variability of the parameter referenced, due to measurement techniques known to the art, i.e., pH, or water content (loss on drying).